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Structural and functional characterisation of HepTH1-5 peptide as a potential hepcidin replacement

Azemin WA, Alias N, Ali AM, Shamsir MS

J Biomol Struct Dyn, 2023 Feb;41(2):681-704.
PMID: 34870559 DOI: 10.1080/07391102.2021.2011415

Hepcidin is a principal regulator of iron homeostasis and its dysregulation has been recognised as a causative factor in cancers and iron disorders. The strategy of manipulating the presence of hepcidin peptide has been used for cancer treatment. However, this has demonstrated poor efficiency and has been short-lived in patients. Many studies reported using minihepcidin therapy as an alternative way to treat hepcidin dysregulation, but this was only applied to non-cancer patients. Highly conserved fish hepcidin protein, HepTH1-5, was investigated to determine its potential use in developing a hepcidin replacement for human hepcidin (Hepc25) and as a therapeutic agent by targeting the tumour suppressor protein, p53, through structure-function analysis. The authors found that HepTH1-5 is stably bound to ferroportin, compared to Hepc25, by triggering the ferroportin internalisation via Lys42 and Lys270 ubiquitination, in a similar manner to the Hepc25 activity. Moreover, the residues Ile24 and Gly24, along with copper and zinc ligands, interacted with similar residues, Lys24 and Asp1 of Hepc25, respectively, showing that those molecules are crucial to the hepcidin replacement strategy. HepTH1-5 interacts with p53 and activates its function through phosphorylation. This finding shows that HepTH1-5 might be involved in the apoptosis signalling pathway upon a DNA damage response. This study will be very helpful for understanding the mechanism of the hepcidin replacement and providing insights into the HepTH1-5 peptide as a new target for hepcidin and cancer therapeutics.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Hepcidins*
In silico analysis prediction of HepTH1-5 as a potential therapeutic agent by targeting tumour suppressor protein networks

Azemin WA, Alias N, Ali AM, Shamsir MS

J Biomol Struct Dyn, 2023 Mar;41(4):1141-1167.
PMID: 34935583 DOI: 10.1080/07391102.2021.2017349

Many studies reported that the activation of tumour suppressor protein, p53 induced the human hepcidin expression. However, its expression decreased when p53 was silenced in human hepatoma cells. Contrary to Tilapia hepcidin TH1-5, HepTH1-5 was previously reported to trigger the p53 activation through the molecular docking approach. The INhibitor of Growth (ING) family members are also shown to directly interact with p53 and promote cell cycle arrest, senescence, apoptosis and participate in DNA replication and DNA damage responses to suppress the tumour initiation and progression. However, the interrelation between INGs and HepTH1-5 remains unknown. Therefore, this study aims to identify the mechanism and their protein interactions using in silico approaches. The finding revealed that HepTH1-5 and its ligands had interacted mostly on hotspot residues of ING proteins which involved in histone modifications via acetylation, phosphorylation, and methylation. This proves that HepTH1-5 might implicate in an apoptosis signalling pathway and preserve the protein structure and function of INGs by reducing the perturbation of histone binding upon oxidative stress response. This study would provide theoretical guidance for the design and experimental studies to decipher the role of HepTH1-5 as a potential therapeutic agent for cancer therapy. Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Hepcidins
Fulltext Malaria is a cause of iron deficiency in African children

Muriuki JM, Mentzer AJ, Mitchell R, Webb EL, Etyang AO, Kyobutungi C, et al.

Nat Med, 2021 Apr;27(4):653-658.
PMID: 33619371 DOI: 10.1038/s41591-021-01238-4

Malaria and iron deficiency (ID) are common and interrelated public health problems in African children. Observational data suggest that interrupting malaria transmission reduces the prevalence of ID1. To test the hypothesis that malaria might cause ID, we used sickle cell trait (HbAS, rs334 ), a genetic variant that confers specific protection against malaria2, as an instrumental variable in Mendelian randomization analyses. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.

Matched MeSH terms: Hepcidins/metabolism
Improvement in the diagnostics of iron deficiency anemia using multiple marker combinations

Yang ES, Kim YS, Park CY, Kim JD, Song HJ

Sains Malaysiana, 2015;44:1653-1659.

Anemia of chronic disease (ACD) frequently occurred in patients with chronic inflammatory diseases and can be treated
by treating the underlying disease. On the other hand, iron-deficiency anemia (IDA), the most common type of anemia,
occurred with iron loss or when the iron requirement of the body was increased. Since the treatment methods for ACD
and IDA differ, it is important to clinically distinguish between the two types of anemia. In this study, we investigated and
evaluated the performance of a number of biomarkers, including ferritin, soluble transferrin receptor (sTfR), hepcidin,
C-reactive protein (CRP) and combination markers containing ferritin for the diagnosis of IDA using serum samples from
Korean patients (80 ACD and 48 IDA Korean patients). Among the single markers, ferritin exhibited the best performance
with 98.58% AUC and 97.50% sensitivity. In this study, a combination of two biomarkers was used to differentially
diagnose IDA and ACD. Among the combination markers, ferritin + sTfR showed the best performance with 99.51% AUC
and 98.75% sensitivity. We found that the ferritin + sTfR combination showed the best diagnostic performance with
1.25% higher SN than ferritin alone. Moreover, it also showed 10% better diagnostic performance than the single ferritin
marker within the data range where the distinction between ACD and IDA is unclear. We propose that using combination
markers containing ferritin may diagnose IDA more accurately and facilitate the determination of the appropriate anemia
treatment to expedite patient recovery.

Matched MeSH terms: Hepcidins
Serum prohepcidin concentrations in rheumatoid arthritis

Jayaranee S, Sthaneshwar P, Sokkalingam S

Pathology, 2009 Feb;41(2):178-82.
PMID: 18972320 DOI: 10.1080/00313020802436840

AIM: Hepcidin, a recently identified peptide, acts as a central regulator of iron metabolism. It is regarded as a factor regulating the uptake of dietary iron and its mobilisation from macrophages and hepatic stores. It is considered as a mediator of anaemia of inflammation. The aim of this study was to assess whether serum prohepcidin concentration is able to distinguish iron deficiency from anaemia of inflammation in patients with rheumatoid arthritis (RA).
METHOD: Blood samples were obtained from 20 healthy blood donors, 30 RA patients who presented with anaemia and 30 patients who had pure iron deficiency anaemia (IDA). The samples were analysed for full blood count, iron, ferritin, transferrin, soluble transferrin receptor and prohepcidin.
RESULTS: The mean prohepcidin level in the control subjects was 256 microg/L. The prohepcidin level was significantly lower in IDA patients (100 microg/L; p < 0.0001) but not significantly different from that of control in RA patients (250 microg/L; p > 0.05). Higher serum soluble transferrin receptor (sTfR) levels were observed in IDA (p < 0.0001) but not in RA compared with that of control (p > 0.05). RA patients were divided into iron depleted and iron repleted subgroups based on the ferritin level. Prohepcidin in the iron depleted group was significantly lower than the iron repleted group and the control (p < 0.0001) and higher levels were observed in the iron repleted group (p < 0.01). sTfR levels in the iron depleted group were significantly higher than the control and the iron repleted patients (p < 0.001). In the iron repleted group, sTfR level was not statistically different from that of control (p > 0.05).
CONCLUSION: Serum prohepcidin is clearly reduced in uncomplicated iron deficiency anaemia. The reduced prohepcidin levels in the iron depleted RA patients suggests that there may be conflicting signals regulating hepcidin production in RA patients. In RA patients who have reduced hepcidin in the iron depleted group (ferritin <60 microg/L) where sTfR levels are increased suggests that these patients are iron deficient. Further studies with a larger cohort of patients are required to substantiate this point.

Matched MeSH terms: Hepcidins